Thyroid Dysfunction in Pregnancy. George R. Saade, M.D.

Thyroid Dysfunction in Pregnancy George R. Saade, M.D.

THYROID ECONOMY IN EARLY PREGNANCY IS AFFECTED BY 3 MAIN FACTORS TBG hcg FT4 ng/dl DIETARY IODINE TSH uu/ml -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 WEEKS GESTATION

TBG AND THYROID FUNCTION (4-10 WKS) Pituitary gland TSH FT 4 Thyroid gland TBG

TBG AND THYROID FUNCTION (4-10 WKS) Pituitary gland TSH FT 4 Thyroid gland TBG NORMAL TSH FT 4

hcg AND THYROID FUNCTION (6-13 WKS) Pituitary gland TSH RECEPTOR TSH FT 4 Thyroid gland hcg NORMAL TSH FT 4

From: Glinoer et al. JCEM 71 : 276 (1990) 50 hcg vs. TSH Changes during Gestation hcg 2.0 40 30 hcg IU/Lx10 3 20 10 TSH 1.5 1.0 TSH miu/l 0.5 0 0.1 1st. Trimester 2nd. Trimester 3rd. Trimester weeks gestation 10 20 30 40

DECREASE THYROID RESERVE chronic thyroiditis post thyroid ablation L-thyroxine Therapy TSH FT4 HIGH TSH NORMAL OR LOW FT 4 CLINICAL OR SUBCLINICAL HYPOTHYROIDISM TBG hcg

TSH uu/ml 8.0 3.0 Normal Thyroid Reserve Decrease Thyroid Reserve 0.4 1.8 FT4 ng/ml 0.6 --2 0 2 4 6 8 10 12 14 16 18 20 30 402 WEEKS GESTATION

Thyroid Disorders in Pregnancy Physiological Changes Non pregnant Pregnant TBG (mg/l) 7 15 20 40 Total T4 ( g/dl) 5 12.5 7 15 Total T3 (ng/dl) 70 200 100 250 Free T4 (ng/dl) 0.8 2.3 0.8 2 Free T3 (ng/dl) 0.25 0.25 TSH (ng/dl) 0.3 0.3 FTI 4.5 12 4.5 12 R3TU (%) 25 35 15 25

Testing for Thyroid Disease Serum TSH Free T4 Free T3

Testing for Thyroid Disease Free thyroxin index FT4I = Total T4 X patient RT3U Normal RT3U

Additional Testing Thyroid peroxidase antibodies (TPO) Previously called thyroid microsomal antibodies TSH receptor antibodies (TRAbs) Blocking (thyrotropin binding inhibitory immunoglobulin (TBII); thyroiditis) Activating (thyroid stimulating immunoglobulin (TSI); hyperthyroidism) Neutral Thyroglobulin antibodies

Radioiodines in Pregnancy Concentrated in fetal thyroid after 12 weeks Excreted in breastmilk Half life 8 days for 131 I (no breastfeeding for 4 weeks) 13.5 hours for 123 I (no breastfeeding for 2 weeks) 6 hours for Tc (no breastfeeding for 2 days)

Hyperthyroidism in Pregnancy 1 per 2000 pregnancies Etiology Graves disease 90% of cases autoimmune disorder may improve in late pregnancy and flare postpartum Toxic diffuse nodule Toxic multinodular goiter Subacute thyroiditis Hashimoto s thyroiditis GTN

Hyperthyroidism in Pregnancy Maternal Risks High output heart failure Thyroid storm (25% mortality)

Hyperthyroidism in Pregnancy Fetal Risks Thyroid antibodies and medications Effect on fetal thyroid unpredictable Neonatal thyrotoxicosis (10% of Graves ) lasts for 2-3 months after delivery TSI not useful may cause craniosynostosis, exophthalmos, heart failure, hepatosplenomegaly Preterm delivery (11-25%) Stillbirths (8-15%) Decreased birthweight

Hyperthyroidism in Pregnancy Diagnosis Signs and symptoms Most confused with pregnancy changes Exophthalmos in Graves Laboratory Free T4 + free T3 (if pregnancy norms available) Ultrasensitive TSH FTI Never use radioactive thyroid scan

Hyperthyroidism in Pregnancy Management FT4 +/- FT3 TSH Both highly abnl Both mildly abnl or Inconsistent Normal Rx rtsh Ab TSI No further testing Positive Negative RX Sx No Sx Rx Follow monthly

Hyperthyroidism in Pregnancy Thioamide Therapy Block incorporation of iodine into tyrosine Propylthiouracil Preferred (also inhibits peripheral conversion of T4 to T3) Start with 100 mg Q 8 Methimazole Start with 10 mg Q 8

Hyperthyroidism in Pregnancy Thioamide Side Effects Skin rash and pruritis Nausea, vomiting, diarrhea Aplasia cutis Agranulocytosis (0.2%) and granulocytopenia (5%) Immediate CBC for sore throat or other Immediate D/C Fetal goiter Transient neonatal hypothyroidism (1-5%)

Hyperthyroidism in Pregnancy Beta Blockers Only for symptomatic relief Also blocks peripheral conversion T4 to T3 Concomitant with thioamides Propranolol Start with 10 mg Q 8 Side effects: bronchospasm, CHF, fetal growth abnormality, neonatal bradycardia, neonatal hypoglycemia

Hyperthyroidism in Pregnancy Antepartum Maternal Follow up If on thioamide and propranolol QOD Adjust by 10 mg Q 8 to maintain pulse < 100 bpm Should be able to D/C in 1-2 weeks If on thioamide only Weekly check for signs and symptoms Laboratory Q 4 weeks Adjust dose by 1/4-1/3 as soon as change Keep FT4 in upper normal range

Hyperthyroidism in Pregnancy Fetal Follow up Ultrasound for growth and neck check Q 3 weeks NST and AFI weekly after 32 weeks

Hyperthyroidism in Pregnancy Postpartum Follow up Effect of immune tolerance decline on Graves disease postpartum Rx Initial diagnosis Flare If breastfeeding similar to antepartum radioiodine contraindicated follow up neonates If not breastfeeding may use radioiodine

Endocrine Society Guidelines de Groot et al. J Clin Endocrinol Metab 2012;97:2543 65

Thyroid Storm General Occurs in 1% of hyperthyroid pregnant women Maternal mortality up to 25% in older literature High risk of heart failure

Thyroid Storm in Pregnancy Precipitating Factors Diabetic ketoacidosis/hypoglycemia Infection (pneumonia, pyelonephritis, meningitis, chorioamnionitis, sepsis) Labor or induction Preeclampsia/Molar pregnancy Pulmonary thromboembolism Trauma and Surgery (including cesarean section)

Thyroid Storm Diagnosis Fever Change in mental status restless nervous confusion seizure coma GI symptoms vomiting diarrhea Tachycardia out of proportion Inciting event

Thyroid Storm Management High index of suspicion Obtain serum FT4, FT3, and TSH prior to therapy Do not wait for laboratory diagnosis Supportive care

Hyperthyroidism in Pregnancy Management of Thyroid Storm Rapid intervention (do not wait for labs) Thioamides PTU 600-800 mg po Methimazole 60-100 mg pr Iodide 1-2 hours after PTU SSKI 2-5 drops po Q 8 NaI 0.5-1 mg IV Q 8 Dexamethasone 2 mg IV Q 6 x 4 doses Propranolol 1-10 mg IV Q 4 IV fluids, electrolytes, antipyretics

Hypothyroidism in Pregnancy Etiology Etiology Autoimmune Postablation Idiopathic Rarely: central

Hypothyroidism in Pregnancy Maternal Risks Myxedema coma (20% mortality)

Hypothyroidism in Pregnancy Fetal Risks Increased SAB Increased stillbirth Neurodevelopmental delay

MATERNAL HYPOTHYROXIDEMIA LOWER IQ S AND INTELLECTUAL DEVELOPMENT OF THE OFFSPRING Matsuura et al: Endocrin Japon 1990;37:369 Mann et al: Ann Clin Lab Sci 1991;21:227 Pop et al: Clin Endoc 1999;50:149 Haddow et al: NEJM 1999:341:549 NORMAL IQ's Lieu et al. Arch Int Med 1994;154:785 Smit et al: Acta Paediatr 2000;89:291

Hypothyroidism in Pregnancy Routine Screening (<16 weeks ) and Treatment Lazarus et al. N Engl J Med 2012;366:493-501 3 years of age

Hypothyroidism in Pregnancy Diagnosis Signs and symptoms Most confused with pregnancy changes Eyelid edema and excessive weight gain Laboratory Free T4 + free T3 if pregnancy norms available Ultrasensitive TSH FTI Never use radioactive thyroid scan

Hypothyroidism in Pregnancy Management FT4 +/- FT3 TSH Both abnl Inconsistent Normal Rx Antimicrosomal Ab Anti-TGB Ab No further testing Positive Negative RX Sx No Sx Rx Follow monthly

Hypothyroidism in Pregnancy Thyroid Hormone Replacement Only use levothyroxine (Synthroid) Start 0.1 mg/d Labs Q 4 weeks Adjust by 1/4-1/3 Postpartum Return to pre-pregnancy dose over 2-4 weeks Labs 4 weeks after stable dose

Postpartum Thyroiditis Affect 5-10% (often subclinical) Initial phase Lymphocytic infiltration of thyroid Thyrotoxicosis (often overlooked or ASx) Starts 6-12 weeks PP and lasts for 4-8 weeks Differentiate from Graves thyroid autoantibodies positive but TSI negative radioiodine uptake decreased Rx symptomatic with beta-blockers Always resolves

Postpartum Thyroiditis Later phase Hypothyroidism Sx confused with postpartum changes (fatigue, weight gain, depression) Starts 3-6 months PP and lasts for 3-6 months Differential Hashimoto s disease (usually permanent) lymphocytic hypophysitis and Sheehan s (TSH elevated) Rx symptomatic with levothyroxine 50% recurrence in future pregnancies

Thyroid Enlargement in Pregnancy Diffuse Normal increase in thyroid size (2x) is barely detectable clinically Any clinically detectable enlargement should be investigated Check iodine intake (developing world) Check TSH and FT4

Thyroid Enlargement in Pregnancy Asymmetrical No radioisotope scanning Ultrasound not very useful for diagnosis Fine needle aspirate Benign Follicular neoplasm (indeterminate) excision vs suppression (risk of carcinoma 20%) Carcinoma (usually papillary) thyroidectomy (may wait if close to term) levothyroxin suppression postpoperative radioablation postpartum

Hyperemesis Gravidarum TSH suppressed in 2/3 of patients Thyroid function tests only if either Prior history Thyroid enlargement Other thyrotoxicosis signs or symptoms Persists beyond 16 weeks Rx only if either Lab abnormality does not improve Dehydration and electrolyte imbalance If Rx: watch for maternal and fetal hypothyroidism